Mutations in BRAF and KRAS converge on activation of the mitogen-activated protein kinase pathway in lung cancer mouse models

Hongbin Ji, Zhenxiong Wang, Samanthi A. Perera, Danan Li, Mei-Chih Liang, Sara Zaghlul, Kate McNamara, Liang Chen, Mitchell Albert, Yanping Sun, Ruqayyah Al-Hashem, Lucian R. Chirieac, Robert Padera, Roderick T. Bronson, Roman K. Thomas, Levi A. Garraway, Pasi A. Jänne, Bruce E. Johnson, Lynda Chin, Kwok Kin Wong*

*此作品的通信作者

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152 引文 斯高帕斯(Scopus)

摘要

Mutations in the BRAF and KRAS genes occur in ∼1% to 2% and 20% to 30% of non-small-cell lung cancer patients, respectively, suggesting that the mitogen-activated protein kinase (MAPK) pathway is preferentially activated in lung cancers. Here, we show that lung-specific expression of the BRAF V600E mutant induces the activation of extracellular signal-regulated kinase (ERK)-1/2 (MAPK) pathway and the development of lung adenocarcinoma with bronchioloalveolar carcinoma features in vivo. Deinduction of transgene expression led to dramatic tumor regression, paralleled by dramatic dephosphorylation of ERK1/2, implying a dependency of BRAF-mutant lung tumors on the MAPK pathway. Accordingly, in vivo pharmacologic inhibition of MAPK/ERK kinase (MEK; MAPKK) using a specific MEK inhibitor, CI-1040, induced tumor regression associated with inhibition of cell proliferation and induction of apoptosis in these de novo lung tumors. CI-1040 treatment also led to dramatic tumor shrinkage in murine lung tumors driven by a mutant KRas allele. Thus, somatic mutations in different signaling intermediates of the same pathway induce exquisite dependency on a shared downstream effector. These results unveil a potential common vulnerability of BRAF and KRas mutant lung tumors that potentially affects rational deployment of MEK targeted therapies to non-small-cell lung cancer patients.

原文English
頁(從 - 到)4933-4939
頁數7
期刊Cancer Research
67
發行號10
DOIs
出版狀態Published - 15 5月 2007

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